Feb 17 May 17 June 17 Aug 17

2.53 cm 1.32 cm 1.04 cm 0.65 cm

1.76 cm 1.28 cm 1.30 cm 1.29 cm

2.54 cm 2.06 cm 1.61 cm 1.34 cm

A First in Human Phase 1 Study of KPT-9274, a First in Class Dual Inhibitor of PAK4 and NAMPT, in Patients with Advanced Solid Malignancies or NHL

Contact Information: Aung Naing, MD (anaing@mdanderson.org)Erkan Baloglu, PhD, MBA (ebaloglu@karyopharm.com)

Copies of this poster obtained through QR (Quick Response) code are for personal use only and may not be reproduced without written permission of the authors

Aung Naing1, Stephen Leong2, Michael J. Pishvaian3, Albiruni Razak4, Amit Mahipal5, Jordan D. Berlin6, Daniel C. Cho7, William Senapedis8, Sharon Shacham8, Michael G. Kauffman8, Joel Ellis8, Julie Meade8, and Erkan Baloglu8

(1) University of Texas, MD Anderson Cancer Center, Houston, TX, USA, (2) University of Colorado Cancer Center, Aurora, CO, USA, (3) Georgetown University, Lombardi Comprehensive Cancer Center, Washington, DC, USA, (4) UHN Princess Margaret Cancer Centre, Toronto, ON, Canada, (5) Mayo Clinic, Rochester, MN, USA, (6) Vanderbilt University Medical Center, Nashville, TN, USA, (7) NYU Langone Medical Center, New York, NY, USA,(8) Karyopharm Therapeutics Inc, Newton, MA, USA

KPT-9274 Mechanism of Action

KPT-9274 Preclinical Activity

Study Design

Biomarker Development

Time on Study, Disease, and Response

Human Pharmacokinetic (PK) Profile of KPT-9274

Related Adverse Events in ≥ 3 Patients

Case Study – Patient 0100-11002

Summary and Conclusions

adapted from Sampath et al., Pharmacology & Therapeutics 2015

adapted from Senapedis et al., Anticancer Agents Med Chem. 2016

Cancer Type Model Dose (mg/kg)

Regimen (per week)

Best Response

Hepatocellular carcinoma Hep 3B 100 BIDx5 37% TGI

Renal cell carcinoma Caki-1 100 BIDx5 46% TGI786-O 100 BIDx5 70% TGI

Triple negative breast cancer MDA-MB-468 100 BIDx7 73% TGIMDA-MB-231 150 BIDx4 84% TGI

Non-small cell lung cancer NCI-H520 100 BIDx5 6% TR

Colorectal carcinoma COLO 205 100 BIDx5 41% TRCOLO 320HSR 200 BID QoDx3 72% TGI

Esophageal Squamous KYSE510 150 BIDx5 90% TRMultiple myeloma MM1.S 100 BIDx5 75% TRT-cell acute lymphoblastic leukemia MOLT-4 100 BIDx7 92% TR

Mantle cell lymphoma Z-138 100 BIDx7 100% TRJeKo-1 200 QoDx3 93% TGIA d re

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KCP-9274-901 is a Phase 1 open-label study of the safety, tolerability, and efficacy of KPT-9274, a 1st in Class dual inhibitor of PAK4 andNAMPT in patients with advanced solid malignancies or NHL

§ Primary Objectives§ Determine the MTD and RP2D for KPT-9274 administered alone (Part A) or in combination with Niacin ER (Part B)§ Evaluate the safety / tolerability including DLT of KPT-9274 +/- Niacin ER and the dosing schedule

§ Dose Limiting Toxicity (DLT) Definition§ DLT is an AE or abnormal laboratory value (NCI CTCAE v. 4.03) that occurs within the first 28 days of treatment with KPT-9274 and

meets the following criteria:§ Gr ≥3 nausea/vomiting, dehydration or diarrhea while taking optimal supportive medications or§ Gr 4 neutropenia lasting > 5 days; febrile neutropenia (ANC<1E9/L, fever>38.5 oC); Gr 4 thrombocytopenia or Gr 3

thrombocytopenia with bleeding, or any requirement for platelet transfusion or Gr 4 anemia, unexplained by underlying disease or§ Any other Gr ≥3 non-hematological toxicity except alopecia or electrolyte abnormalities correctable with supportive therapy

Part AKPT-9274 Single Agent

To determine the RP2D or MTD of KPT-9274

KPT-9274 ± Niacin ER1. NAPRT1+ (N ~ 10)2. NAPRT1- (N ~ 10)3. NAPRT1 +/- (N ~ 10)4. IDH1 mutant (N ~ 15)

Dose Escalation ExpansionPart B

KPT-9274 + Niacin ERTo determine the RP2D or

MTD of KPT-9274 + Niacin ER

Characteristic Dose Escalation (N=21)

Median Age (Range) 61 ( 28 – 74 )Male : Female 14 : 7

Median Prior Regimens (Range) 6 ( 1 – 11 )Median Days on Treatment (Range) 57 ( >1 – 226 )

Disease Refractory to Last Therapy % 100%

Cohort Dose / Schedule Patients Enrolled

1 10 mg / qodx3 32 20 mg / qodx3 33 30 mg / qodx3 54 40 mg / qodx3 7

3B 30 mg / qodx3 + 500 mg Niacin 3

as of 10 July 2017

§ Patients with advanced solid malignancies or NHL for which all standard therapeutic options have been exhausted§ Patients must have:

§ objective evidence of progressive disease on study entry§ a site of disease amenable to biopsy and be a candidate for biopsy according to the treating institution’s guidelines§ adequate hematopoietic, hepatic, and renal function§ NAPRT1 and IDH1 tumor status determined (for KPT-9274 + Niacin ER cohorts)

§Plasma levels at 30 and 40 mg appear dose-proportional to 10 mg§There is substantial accumulation across the 26-day dosing regimen

§The Cmax (and accurate AUC) is likely missed; t1/2 not determined§Sampling adjustments to better characterize are implemented

Dose (mg) Cmax (ng/mL) Tmax (h) AUC0-inf (ng*h/mL)10 152 8 4,43520 79.4 8 2,61730 411 24 12,58040 565 8 18,709

PK Parameters – Day 1 PK Parameters – Day 24Dose (mg) Cmax (ng/mL) Tmax (h) AUC0-inf (ng*h/mL)

10* 256 4 1,61420 319 8 10,45630 1,281 19 48,14640 1,550 5 53,430

* Day 26

§ Increased NAPRT1 promotermethylation correlates withdecreased NAPRT1 expression andlack of rescue with niacin

§ 25 to 30% hyper-methylation is thecutoff for the level of methylation innormal tissue

Additional Patients with no Tumor Measurements

§ In patients whose disease has progressed despite most available therapies, KPT-9274 induces disease stabilization§ Dose escalation is on-going in Part A (without Niacin) and in Part B (with Niacin)§ KPT-9274 is well tolerated across different indications; one DLT (anemia) observed to date§ The most common AEs are anemia, arthralgia, and fatigue§ GI related AEs are infrequent and low grade§ Niacin can safely be given with KPT-9274 and may improve KPT-9274 tolerability§ NAPRT1 status may predict response to KPT-9274 ± Niacin

§ Although expected, no significant GI toxicity or thrombocytopenia observed§ The most common AEs include anemia, arthralgia, and fatigue

§ No drug related AEs observed at 10 mg§ 1 DLT at 40 mg (G4 anemia)

Mechanism of Action of KPT-9274§ KPT-9274 is an oral, small molecule modulator of

PAK4 (p21 activated kinase) and NAMPT(nicotinamide phosphoribosyltransferase)

§ PAK4 is a major player in cell morphology andWNT/β-catenin signaling

§ NAMPT is the rate-limiting enzyme in NADbiosynthesis

§ Co-inhibition of these targets leads to synergistic anti-tumor effects through energy depletion, inhibition ofDNA repair, cell cycle arrest, and ultimately apoptosis

§ Cells can utilize niacin to make NAD through analternative pathway using NAPRT1, which is oftenabsent in tumors making it a potential responsebiomarker

§ KPT-9274 demonstrates potent anti-tumor activitypre-clinically and in patient dogs with cancer

Mechanism of Action of PAK4 Modulation Mechanism of Action of NAMPT Inhibition

Adverse Events

All Dose Levels (N=21)

10 mg (N=3)

20 mg (N=3)

30 mg (N=5)

40 mg (N=7)

30 mg + Niacin (N=3)

G1/2 G3 G4 Total All G1/2 G3 G1/2 G3 G1/2 G3 G4 G1/2Anemia 5 (24%) 7 (33%) 1 (5%) 13 (62%)

No E

vents

1 1 1 2 2 4 1 1Arthralgia / Arthritis 9 (43%) 9 (43%) 3 5 1

Fatigue 5 (24%) 1 (5%) 6 (29%) 1 1 3 1Diarrhea 4 (19%) 4 (19%) 1 2 1Myalgia 4 (19%) 4 (19%) 2 1 1

ALT increased 3 (14%) 3 (14%) 2 1Edema 3 (14%) 3 (14%) 1 1 1

Dizziness 3 (14%) 3 (14%) 1 2Flushing* 3 (14%) 3 (14%) 1 2Dyspnea 3 (14%) 3 (14%) 2 1

Adverse Events (AEs) Summary (as of 10 July 2017)

Prior Therapies§ 56 year old man diagnosed with intraocular (uveal) melanoma (2009) metastatic to the liverand lungs (2016), GNAQ mutated, NAPRT1-,

§ Comorbidities: Controlled atrial fibrillation and arthritis.§ Joined the study in March, 2017 (single agent KPT-9274; 3 prior chemotherapy regimens).§ Dose interruption/reduction due to anemia/fatigue, recovered with niacin supplementation,

continuing active daily life.§ On study (>175 days; last seen on 22 Aug 2017; SD (-22.6%).

Patient ID NAPRT1 Status

Disease Assessment

0001-11005 - NE

0002-11002 + NE

0100-11003 + PD

0100-11004 + Pending

IC50

(µM)

as of 10 July 2017

In vitro potency of KPT-9274 in cancer cell lines Anti-tumor activity of oral KPT-9274 in a variety of mouse xenografts models

Patient Population

Feb 17 May 17 June 17 Aug 17

2.53 cm 1.32 cm 1.04 cm 0.65 cm

1.76 cm 1.28 cm 1.30 cm 1.29 cm

2.54 cm 2.06 cm 1.61 cm 1.34 cm

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Feb 17 May 17 June 17 Aug 17

2.53 cm 1.32 cm 1.04 cm 0.65 cm

1.76 cm 1.28 cm 1.30 cm 1.29 cm

2.54 cm 2.06 cm 1.61 cm 1.34 cm

Feb 17 May 17 June 17 Aug 17

2.53 cm 1.32 cm 1.04 cm 0.65 cm

1.76 cm 1.28 cm 1.30 cm 1.29 cm

2.54 cm 2.06 cm 1.61 cm 1.34 cm

* Pts receiving Niacin

Regimen Treatment Start Date Days on Treatment

Best Response

1 Cabozantinib 29-Feb-16 66 SD

2 Ipilimumab 31-May-16 1 Unk

3 Pembrolizumab 23-Jun-16 233 Unk

4 KPT-9274 13-Mar-17 >175 SD